Integrating Synthetic Biology, Systems Biology, and Bioprocessing to Advance Terpene Production in Cyanobacteria

Abstract Cyanobacteria act as efficient “solar-powered” cell factories, converting CO2 and light into valuable products while thriving in seawater or wastewater. Cyanobacteria are attractive hosts for terpenoid bioproduction because they natively produce terpene precursors. Our review found that while cyanobacteria have been engineered to produce 26 different terpenoids, only 1 of the 63 terpene bioproduction studies achieved titers in the g/L range. To identify the path forward towards maximizing cyanobacterial terpene titers and productivity, this review has taken a twofold approach. First, it synthesizes progress and bottlenecks across three interconnected dimensions: synthetic biology, systems biology, and bioprocess engineering. Second, it addresses a limitation of the field by harmonizing all cyanobacterial terpenoid bioproduction titers into consistent units for the first time, enabling like-for-like comparisons. Through this, three factors were found consistent across the top five highest titers: terpene precursor overexpression, fermentation optimization (using nutrient-rich media and/or a bioreactor), and the production of a volatile terpenoid. On the other hand, while systems biology-informed metabolic engineering can significantly increase cellular health and productivity, it is the least utilized strategy. Taken together, this review highlights the importance of multifaceted approaches to improving cyanobacterial terpene production.